Image info The image shows reconstitution of a rat skull by micro computed tomography (microCT). The mineralised part of the bone appears in white. Two circular bone defects on the calvaria were regenerated after two months by the local delivery of engineered human growth factors. Mikaël Martino

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Martino Group

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The Martino group combines research in immunology, stem cells, and bioengineering, in order to understand the molecular and cellular mechanisms governing tissue repair and regeneration. Using the findings from the lab, the group aims at engineering novel regenerative strategies.

Research

To design successful regenerative therapies and make regenerative medicine a more widespread reality, we need to understand how our body is able to create an environment suitable for regeneration. For instance, tissue injury and the healing process are usually accompanied with the activation of our immune system. The type of immune response, its duration, and the cells involved can considerably change the outcome of the healing process from incomplete restoration (causing scarring/ fibrosis and loss of function) to complete recovery (regeneration).

One of the main goals of the group is to reveal the key mechanisms by which the immune system leads to tissue repair or regeneration. Our research tools include genetically modified and chimeric mice as well as injury models in tissues such as bone, skin and muscle. Ultimately, the group seeks to engineer efficient regenerative strategies that integrate control of the immune system using various bioengineering approaches (such as biomaterials, protein engineering or immunoengineering).

1. Dissecting how the immune system modulates tissue repair and regeneration

Tissue injury and the healing response is usually accompanied with the activation of the immune system. The type of immune response, its duration, and the cells involved can considerably change the outcome of the healing process from incomplete restoration (i.e. scarring/fibrosis and loss of function) to complete recovery (i.e. regeneration) [1] (Fig. 1).

Our group aim at uncovering key mechanisms by which our immune system modulates tissue repair and regeneration. For example, we found that inflammatory pathways involving the cytokine IL-1β inhibit the regenerative capacity of endogenous and transplanted stem cells. We could significantly improve stem cell-driven bone regeneration by engineering a stem cell delivery system that integrate an inhibitor of the IL-1β signalling pathway [2] (Fig. 2).

Figure 2

In addition to the innate immune system, the adaptive immune system – in particular T lymphocytes – is most likely a key actor in the tissue healing process [1]. For instance, we aim at understanding how the adaptive immune system modulates tissue repair and regeneration. Ultimately, we seek to use bioengineering approaches involving biomaterials, protein engineering, and immunoengineering to design novel regenerative therapies (Fig. 3).

Figure 3

2. Better delivery system for stem cells and pro-regenerative molecules

Stem cells and morphogens such as growth factors are obviously very promising for regenerative medicine. However, how can we actually create efficient and safe regenerative therapeutics based on stem cells or growth factors? While the first challenge is to find the right stem cell or the right morphogen for a particular application in regenerative medicine, the second challenge is to develop an appropriate and safe way to deliver these therapeutics. For example, stem cells need to survive and integrate in the host tissue after implantation, while morphogens need to signal in a controlled manner to stimulate endogenous regenerative pathways [3-9]. In addition, both stem cells and morphogens must display very limited side effects. To tackle these challenges, our group is developing delivery systems for stem cells and growth factors that are designed to maximize their therapeutic potential while limiting their side effects. For example, bone regeneration induced by mesenchymal stem cells has been significantly improved by limiting the inflammatory effect on stem cells [2]. Growth factor efficiency in promoting bone regeneration or chronic wound repair has been considerably enhanced by engineering growth factors to process a “built-in” delivery system which target the endogenous extracellular matrix in our tissue [7] (Fig. 4).

Martino MM, Briquez PS, Ranga A, Lutolf MP, Hubbell JA, Heparin-binding domain of fibrin(ogen) binds growth factors and promotes tissue repair when incorporated within a synthetic matrix. Proceedings of the National Academy of Sciences of the United States of America 110, 4563-4568 (2013).